MTMR6 downregulation contributes to cisplatin resistance in oral squamous cell carcinoma.

IF 6 2区医学 Q1 ONCOLOGY Cancer Cell International Pub Date : 2025-01-31 DOI:10.1186/s12935-025-03654-9

Kah Young Lee, Su Young Oh, Heon-Jin Lee, Tae-Geon Kwon, Jin-Wook Kim, Chang-Geol Shin, Su-Hyung Hong, So-Young Choi

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Abstract

Background: The therapeutic effectiveness of cisplatin, a widely used chemotherapy drug for oral squamous cell carcinoma (OSCC), is often compromised by resistance, making it difficult to predict treatment outcomes. The role of myotubularin and myotubularin-related (MTMR) genes in cisplatin resistance remains unclear. We aimed to elucidate the molecular mechanisms underlying MTMR6 with cisplatin resistance in OSCC.

Methods: MTMR6 expression was compared between UMSCC1 and cisplatin-resistant UM-Cis cells. Gain- and loss-of-function experiments involving MTMR6 was performed to evaluate its impact on cisplatin resistance. The regulatory role of hsa-miR-544a on MTMR6 expression was explored via antagomir and miRNA mimic assays. The relationship between MTMR6 protein levels and cisplatin sensitivity was assessed in OSCC patient tissues classified as sensitive or resistant to cisplatin monotherapy. A survival analysis based on The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) dataset was performed to evaluate the correlation between MTMR6 expression and patient outcomes following cisplatin treatment. In vivo cisplatin resistance was examined using mouse xenografts derived from MTMR6-knockdown UMSCC1 cells.

Results: MTMR6 expression was markedly reduced in cisplatin-resistant UM-Cis cells compared to UMSCC1 cells. Functional analyses revealed that modulating MTMR6 activity alters cisplatin resistance. A luciferase assay confirmed that hsa-miR-544a regulates MTMR6 gene expression. Additionally, antagomir and miRNA mimics demonstrated that hsa-miR-544a enhances cisplatin resistance by suppressing MTMR6 expression. In OSCC patient tissues, higher MTMR6 protein levels were associated with cisplatin sensitivity, while cisplatin-resistant tissues had lower MTMR6 expression. Survival analysis of the TCGA HNSCC dataset indicated that low MTMR6 expression correlates with poorer outcomes in cisplatin-treated patients compared to those with high MTMR6 expression. Mouse xenografts derived from MTMR6-knockdown UMSCC1 cells exhibited increased resistance to cisplatin compared to controls.

Conclusion: Assessing mRNA levels of MTMR6 and has-miR-544a in biopsy samples could help predict cisplatin responsiveness in OSCC.

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MTMR6下调有助于口腔鳞状细胞癌顺铂耐药。

背景：顺铂是口腔鳞状细胞癌（OSCC）广泛使用的化疗药物，其治疗效果经常受到耐药性的影响，使得治疗结果难以预测。肌管蛋白和肌管蛋白相关（MTMR）基因在顺铂耐药中的作用尚不清楚。我们的目的是阐明MTMR6与OSCC顺铂耐药的分子机制。方法：比较MTMR6在UMSCC1和顺铂耐药UM-Cis细胞中的表达。我们进行了MTMR6的功能增益和功能丧失实验，以评估其对顺铂耐药性的影响。hsa-miR-544a对MTMR6表达的调节作用通过安他哥米和miRNA模拟实验进行了探讨。在对顺铂单药敏感或耐药的OSCC患者组织中评估MTMR6蛋白水平与顺铂敏感性之间的关系。基于癌症基因组图谱（TCGA）头颈部鳞状细胞癌（HNSCC）数据集进行生存分析，以评估顺铂治疗后MTMR6表达与患者预后之间的相关性。使用mtmr6敲除的UMSCC1细胞衍生的小鼠异种移植物检测体内顺铂耐药性。结果：与UMSCC1细胞相比，MTMR6在顺铂耐药UM-Cis细胞中的表达明显降低。功能分析显示，调节MTMR6活性可改变顺铂耐药性。荧光素酶测定证实hsa-miR-544a调节MTMR6基因表达。此外，安塔戈米尔和miRNA模拟实验表明，hsa-miR-544a通过抑制MTMR6表达增强顺铂耐药。在OSCC患者组织中，较高的MTMR6蛋白水平与顺铂敏感性相关，而顺铂耐药组织中MTMR6表达较低。TCGA HNSCC数据集的生存分析表明，与MTMR6高表达的患者相比，顺铂治疗的患者MTMR6低表达与较差的预后相关。与对照组相比，来自mtmr6敲除的UMSCC1细胞的小鼠异种移植物对顺铂的抗性增加。结论：评估活检样本中MTMR6和has-miR-544a的mRNA水平有助于预测OSCC的顺铂反应性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.